Photodynamic diagnosis (PDD) is a technique for the identification of metabolically active cells. Examples of metabolically active cells are cells which undergo an abnormal growth pattern. Such abnormal growth patterns include an increased number of cells/increased cell proliferation (hyperplasia), abnormal maturation and differentiation of cells (dysplasia) and abnormal proliferation of cells (neoplasia). The cells of a hyperplastic growth remain subject to normal regulatory control mechanisms. Cells of a neoplastic growth are genetically abnormal cells which proliferate in a non-physiological manner which is unresponsive to normal stimuli. Other examples of metabolically active cells are inflamed cells or infected cells. Hence PDD can be used for the diagnosis of pre-cancerous lesions, cancer and non-cancerous diseases.
PDD involves the administration of a photosensitizer or a precursor thereof to an area of interest. The photosensitizer or precursor thereof is taken up into the cells, where a precursor of a photosensitizer is converted into a photosensitizer. Upon exposure of the area of interest to light, the photosensitizer is excited and displays in response a fluorescence which is detected. The photosensitizer accumulates preferentially in metabolically active cells and tissue, such as inflamed or neoplastic tissue; hence such tissue can be distinguished from healthy tissue. Studies suggest that accumulation is not due to selective uptake by metabolically active, e.g. cancerous cells, rather, there are similar levels of uptake in all cell types, but the processes of conversion and elimination are different in metabolically active cells, such as neoplastic tissue, leading to a concentration gradient of photosensitizer between e.g. inflamed/neoplastic and normal tissue.
Several photosensitizers and precursors thereof are known and described in the literature, including 5-aminolevulinic acid (5-ALA) and certain derivatives thereof, e.g. 5-ALA esters, both of which are precursors of photosensitizers. These are converted intracellularly to protoporphyrins, such as protoporphyrin IX (PpIX), which are photosensitizers. Currently several pharmaceutical products comprising 5-ALA or an ester thereof are in clinical use for (PDD) but also for photodynamic therapy (PDT). One of them is Metvix®, a dermal product in the form of a cream comprising the hydrochloride salt of methyl 5-ALA ester (i.e. methyl-5-aminoveluvinate hydrochloride), developed by Photocure ASA, Norway, and now sold by Galderma, Switzerland, for the photodynamic therapy of actinic keratosis and basal cell carcinoma. Another one is Levulan Kerastick® (DUSA Pharmaceuticals, Canada), a product for the photodynamic therapy of actinic keratosis which contains the hydrochloride salt of 5-ALA. Hexvix® (Photocure ASA) is an aqueous solution which comprises the hydrochloride salt of hexyl 5-ALA, i.e. hexyl-5-aminolevulinate hydrochloride (HAL) for instillation into the bladder for diagnosis of bladder cancer.
There is an ongoing need to provide a convenient ready-to-use form of a PDD and/or PDT compound, e.g., that also allows the compositions to be prepared with a reliable and accurate concentration, which would be useful in the treatment and diagnosis of the majority of diseases, including cancer where it can be critical that the correct and efficient dosage of therapeutic or diagnostic is administered.
The present invention thus provides a novel crystalline polymorphic form of hexyl-5-aminolevulinate hydrochloride. Said novel crystalline polymorphic form of hexyl-5-aminolevulinate hydrochloride is useful in PDT and PDD.
Crystalline polymorph forms of a particular drug can be determinant of the drug's ease of preparation, stability, solubility, storage stability, ease of formulation and in vivo pharmacology. Polymorphic forms occur where the same composition of matter crystallizes in a different lattice arrangement resulting in different thermodynamic properties and stabilities specific to the particular polymorph form. Different polymorphs of a given compound may differ from each other with respect to one or more physical properties, such as solubility and dissociation, true density, crystal shape, compaction behavior, flow properties, and/or solid state stability.